The 2017 Phillip A. Sharp Awards for Innovation in Collaboration

Interrogation of Resistance Mechanisms to Checkpoint Inhibitors Using Functional Genomics

Siwen Hu-Lieskovan, MD, PhD, University of California Los Angeles

Rene Bernards, PhD, Netherlands Cancer Institute

Grant Term: July 2017 - June 2019 Total Funding: $250,000

Project SummaryThe excitement over the success in clinical development of PD-1 checkpoint inhibitors in multiple tumor types is dampened by low response rate. It is imperative to understand why some patients do not respond (primary resistance) or why some patients who had an initial response eventually relapsed (secondary resistance). In this project, the team analyzes samples from patients treated with anti-PD-1 to identify genes that may be responsible for resistance to immunotherapy. They will use the new gene editing technology called CRISPR to verify which genes in cancer cells protect the cancer from being killed by the T cells.

Progress UpdateThe team has identified 200 genes in samples from melanoma patients treated with anti-PD-1 that may be responsible at least in part for observed secondary resistance. The team is performing cell experiments to identify the genes that enable escape from T-cell killing.

Dissecting the epigenetic mechanisms of repeat RNA regulation in cancer

David T. Ting, MD, Massachusetts General Hospital

Shelley Berger, PhD, University of Pennsylvania

Grant Term: July 2017 - June 2018Total Funding: $250,000

Project SummaryThere are short sequences in the DNA that are repeated. One of these repetitive sequences is called HSATII. Increased levels of HSATII have been found in cancer samples. The levels of HSATII can be reduced by inhibitors of the enzyme called nucleoside reverse transcriptase (these inhibitors have been used as part of the treatment of HIV/AIDS). There is evidence that the tumor suppressor protein p53, which is frequently mutated in cancer, can also affect the levels of HSATII.

AccomplishmentsPrevious laboratory studies showed that colon cancer cell lines with a p53 mutation were susceptible to nucleoside reverse transcriptase inhibitors (NRTI). The team confirmed in animal studies that the NRTI called lamivudine significantly reduced tumor growth of colon cancer cells with a p53 mutation. A phase II trial at MGH has been opened where the lamivudine is tested in p53 mutant colon cancer. Nine patients were enrolled using the maximum FDA approved oral dose of 300 mg daily. Two of nine patients treated with lamivudine had stable disease for six months.

Probing the metabolic interactions between tumor and stroma in pancreatic cancer

Matthew G. Vander Heiden, PhD, Massachusetts Institute of Technology

Melissa C. Skala, PhD, Morgridge Institute for Research

Grant Term: July 2017 - June 2019 Total Funding: $250,000Project SummaryThe team hypothesizes that cells in the tumor microenvironment of pancreatic cancer cells (called stromal cells) enable pancreatic cancer cells to produce the building blocks the cancer cells need. They seek to understand the interactions between pancreatic cancer and stromal cells using 3D cell cultures called organoids. The team is studying how nutrients are shared between cancer cells and stromal cells.

AccomplishmentsThe team confirmed that the cells in the tumor microenvironment can actually promote the growth of the tumor. They observed that co-injection in mice of stromal cells called pancreatic stellate cells, together with cancer cells, accelerated tumor growth.